Dopamine has been implicated as one of the primary neurotransmitters responsible for mediating the reinforcing properties of various substances of abuse, including ethanol. We have investigated the effect of local ethanol perfusion into the terminal regions of the nucleus accumbens and corpus striatum. We have demonstrated that ethanol increases local concentrations of extracellular dopamine in a dose-related fashion. This effect was demonstrated to be both pharmacologically and physiologically relevant to man since it required normal calcium channel function and occurred at brain concentrations of ethanol which can be considered to be similar to intoxication levels in man. Furthermore, we were able to demonstrate a structure-activity relation with regard to the number of carbon atoms possessed by the alcohol. Pretreatment with antagonists of 5-HT3 receptors effectively attenuated the ethanol-induced dopamine increase, suggesting a potential role for serotoninergic mediation or modulation of the ethanol induced dopamine response. Similarly, pretreatment with a 5-HT3 antagonist apparently attenuated ethanol induced hypothermia but no hyperlocomotion in mice. We are attempting to further clarify the nature of this ethanol effect on dopamine both in the acute challenge and in animals receiving chronic ethanol.